Discovery and validation of biomarkers of autoimmunity in Alzheimer's Disease.

R21项目摘要 阿尔茨海默病是一种严重的神经退行性疾病，影响数百万人。目前有 没有有效的治疗方法，对疾病的管理依赖于准确的诊断， 评估进展。在我们的拨款申请中，我们的目标是确定鉴别诊断的生物标志物 阿尔茨海默病和其他神经退行性疾病之间的联系， 非侵入性地评估疾病的进展。我们假设阿尔茨海默病是 发病机制是多因素的，包括经典的淀粉样蛋白假说和其他不断发展的假说。 我们假设至少有一部分患者由于自身抗体之间的自身免疫反应而发展为AD 存在于脑脊髓液（CSF）中的抗脑特异性蛋白质。我们的初步研究表明 清楚地表明，一些阿尔茨海默病患者拥有自身抗体或自身免疫性抗体， 脑脊液中的复合物通过使用最先进的质谱法，我们将识别这种 自身抗体或免疫复合物的发现阶段，使用高灵敏度和特异性的测定， 最近开发的。一旦我们确定了脑脊液中的候选分子，我们将与 一家名为MesoScale Diagnostics的公司，开发针对约10种自身抗体/免疫复合物的靶向检测方法 可以首先在脑脊液中进行评估，然后在血清中进行评估。与一个优秀的生物银行合作， 西班牙巴塞罗那（合作者Morato博士），我们将从以下医院获得高质量的样本，并附有临床注释： 没有阿尔茨海默病的患者，患有轻度、中度和重度阿尔茨海默病的患者以及患有 进行性或非进行性疾病。通过使用这些有价值的样本， 第一年进行实验，第二年进行靶向测定开发。一旦我们完成 这些目标，我们打算土堆一个广泛的验证过程，以确定一组 可用于AD疾病鉴别诊断和监测的自身抗原/免疫复合物 进展我们相信，我们发现的生物标志物将是临床试验的基础， 新的药物可能能够减缓或阻止疾病的早期阶段。

R21 Project summary abstract Alzheimer’s disease is a serious neurodegenerative disorder affecting millions of people. Currently there are no effective therapies and the reliance on managing the disease depends on accurate diagnosis and assessment of progression. In our grant application we aim to identify biomarkers for differential diagnosis between Alzheimer’s disease and other neurodegenerative disorders and also, biomarkers that are able to non-invasively assess the progression of the disease. We postulate that Alzheimer’s disease is pathogenesis is multifactorial and includes the classical amyloid hypothesis and other, evolving hypotheses. We postulate that at least some patients develop AD due to autoimmune reactions between autoantibodies present in cerebral spinal fluid (CSF) against brain specific proteins. Our preliminary studies have clearly shown that some patients with Alzheimer’s disease possess either autoantibodies or autoimmune complexes in cerebral spinal fluid. By using state-of-the-art mass spectrometry we will identify such autoantibodies or immune complexes in a discovery phase, using a highly sensitive and specific assay that we recently developed. Once we identify candidate molecules in cerebral spinal fluid we will collaborate with a company, MesoScale Diagnostics, to develop targeted assays for about10 autoantibodies/immune complexes that can be assessed first in cerebral spinal fluid and later in serum. In association with an excellent biobank in Barcelona Spain (collaborator Dr. Morato) we will obtain high quality samples with clinical annotations from patients without Alzheimer disease, with mild moderate and sever Alzheimer disease and patients who have progressive or non-progressive disease. By using these valuable samples we will do the discovery experiments the first year followed by targeted assay development in the second year. Once we complete these objectives we intend to mound an extensive validation process to identify a group of autoantigens/immune complexes that can be used for differential diagnosis and monitoring of AD disease progression. We believe that our discovered biomarkers will be fundamental in clinical trials which are testing new agents which may be able to slow down or halt the disease at an early stage.